The invention relates to a new process for the preparation of (1xe2x80x2-tert-butoxycarbonyl-2-oxo-[1,3xe2x80x2]-bipyrrolidinyl-3-(R,S)-yl)-triphenyl-phosphonium halogenide compounds of formula I 
wherein * signifies an asymmetric center with an (R) or (S) configuration and X represents chlorine, bromine or iodine.
The compounds of formula I are known from EP-A 0 849 269 and can be obtained through multiple-step synthesis of the corresponding allyloxycarbonyl (ALLOC) protected [1,3xe2x80x2]bipyrrolidinyl-2-oxo derivative by removal of the allylocycarbonyl protecting group and protection reaction with a tert-butoxycarbonyl moiety to yield tert-butoxycarbonyl (t-BOC) protected [1,3xe2x80x2]bipyrrolidinyl-2-oxo compounds of formula I.
It has now been found that the compounds of formula I can be manufactured in an improved and shortened way by the process of the present invention. The new process for the preparation of (1xe2x80x2-tert-butoxycarbonyl-2-oxo-[1,3xe2x80x2]-bipyrrolidinyl-3-(R,S)-yl)-triphenyl-phosphonium halogenide compounds of formula I 
wherein * signifies an asymmetric center with an (R) or (S) configuration and X represents chlorine, bromine or iodine; comprises
step 1) coupling N-benzyl-3-pyrrolidinamine of formula II 
wherein * is as defined above with a compound of formula X(CH2)2CH(X)COX
wherein X is independently of each other chlorine, bromine or iodine; and subsequent cyclization in the presence of a base to obtain a compound of formula III 
wherein * and X are as defined above;
step 2) reacting the compound of formula III with triphenylphosphine to obtain the phosphonium salt of formula IV 
wherein * and X are as defined above; and
step 3) reacting the phosphonium salt of formula IV with di-tert.-butyl-dicarbonate under hydrogenation conditions to obtain the compounds of formula I.
Surprisingly, it has been found that the N-benzyl-3-pyrrolidinamine of formula II undergoes the reaction sequence described above to yield the compounds of formula I, despite the expected instability of intermediate III. The corresponding t-Boc and Alloc protected derivatives of starting material of formula II are not available through the described process.
In the structural formulae of the compounds given throughout this application, a wedged bond () indicates a substituent which is above the plane of the paper.
In the structural formulae of the compounds given throughout this application, a dotted bond () indicates a substituent which is below the plane of the paper.
The compounds of the present process invention exhibit stereoisomerism and can be any stereoisomer. The compounds of the present process invention having one asymmetric carbon atom may be obtained as racemic mixtures of stereoisomers which can be resolved, at the appropriate steps in the process of this invention by methods well known in the art to obtain a given stereoisomer or pure enantiomer having a desired stereoconfiguration. Alternatively, the desired isomers may be directly synthesized by methods known in the art.
The asymmetric carbon atom in the compound of the present invention is denoted as xe2x80x9c*xe2x80x9d. The stereoconfiguration of the asymmetric carbon atom denoted as xe2x80x9c*xe2x80x9d can be designated according to the particular stereoisomer it represents. Compounds of the present invention include those compounds wherein the carbon atom denoted as xe2x80x9c*xe2x80x9d have the S, R or R,S-configuration, preferably the R-configuration.
The term halogen stands for chlorine, bromine and iodine, more preferred chlorine or bromine, most preferred halogen is bromine.
The compounds of the present invention are prepared as shown in the reaction scheme 1.
Reaction Scheme 1: 
wherein * and X are as defined above.
In the 1st step of the reaction the compound of formula II is coupled with 1-4 equivalents, preferably 1-2 equivalents of X(CH2)2CH(X)COX wherein X is independently of each other chlorine or bromine or iodine, preferably bromine (preparation see below) in the presence of bases such as Na3PO4, K2CO3, Na2CO3, KOH or NaOH, preferably Na3PO4 and an appropriate solvent. Appropriate solvents are polar aprotic solvents such as acetonitrile (CH3CN), dimethylsulfoxide (DMSO), dimethylacetamide or N,N-dimethylformamide (DMF), preferably CH3CN. The reaction is carried out at a reaction temperature between about xe2x88x9220xc2x0 C. and about 30xc2x0 C., preferably at a reaction temperature between about xe2x88x9210xc2x0 C. and about 10xc2x0 C. Subsequently, a cyclization reaction is carried out with the intermediate coupling product to obtain compounds of formula III. The cyclization reaction is carried out in the presence of 1-3 equivalents, preferably 2-2.5 equivalents of a base, such as K2CO3, Na2CO3, KOH or NaOH, preferably NaOH in aqueous solution, at a reaction temperature between about xe2x88x9210xc2x0 C. and about 50xc2x0 C., preferably between about 10xc2x0 C. and about 30xc2x0 C.
Compounds of formula X(CH2)2CH(X)COX wherein X is independently of each other chlorine or bromine or iodine are commercially available or are synthesized according to methods known from textbooks. For example the compound of formula X(CH2)2CH(X)COX wherein X is chlorine is prepared according to Mathew, K. K. et al. Indian J. Chem., Sect. B (1981), 20B(4), 340-2. The compound of formula X(CH2)2CH(X)COX wherein X is bromine is prepared according to Marinelli, E. R. et al. Tetrahedron (1996), 52(34), 11177-11214. The compound of formula X(CH2)2CH(X)COX wherein X is iodine can be obtained by reacting the tribromide (Xxe2x95x90Br) with NaI in CH3CN.
In a preferred embodiment of the invention the compound of formula IIIa 
is formed according to the above described 1st step of the reaction. The compound of formula IIIa is new and therefore part of the present invention.
In the 2nd step of the process the compound of formula III is reacted with 1-5 equivalents, preferably 2-4 equivalents of triphenylphosphine to obtain the phosphonium salt of formula IV. The reaction is carried out in an aromatic solvent such as toluene, o-xylene, m-xylene, p-xylene or benzene, preferably toluene at a reaction temperature between about 20xc2x0 C. and about 180xc2x0 C., preferably between about 80xc2x0 C. and about 140xc2x0 C.
In a preferred embodiment of the invention the compound of formula IVa 
is formed according to the above described 2nd step of the reaction. The compound of formula IVa is new and therefore part of the present invention.
In the 3rd step of the process the phosphonium salt of formula IV is reacted with 1-5 equivalents, preferably 2-4 equivalents of di-tert.-butyl-dicarbonate (commercially available from Fluka) under hydrogenation conditions in the presence of a catalyst such as Pd/C (commercially available from Degussa) preferably with 10% Pd on activated carbon, to obtain compounds of formula I. The reaction is carried out in an alcoholic solvent such as methanol, ethanol or isopropanol, preferably in methanol at a reaction temperature between about 10xc2x0 C. and about 100xc2x0 C., preferably between about 40xc2x0 C. and about 80xc2x0 C.
In a preferred embodiment of the invention steps 1-3 are carried out for compounds wherein * signifies an asymmetric center with (R) configuration and X is chlorine or bromine, preferably bromine.
Compounds of formula II, used as starting material in the present process is prepared according reaction steps axe2x86x92bxe2x86x92c as shown in reaction scheme 2. The preparation of the compound of formula II is also part of the present invention.
Reaction Scheme 2: 
wherein R1 is alkyl, R2 is an amino protecting group and * is as defined above.
The terms which have already been mentioned and will be mentioned in the description of the invention are defined as follows:
The term xe2x80x9calkylxe2x80x9d as used herein denotes an optionally substituted straight or branched chain hydrocarbon residue containing 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and its isomers.
Alkyl in R1 is preferably unsubstituted straight or branched chain hydrocarbon residue containing 1 to 4 carbon atoms, more preferred methyl or ethyl, and most preferred methyl.
The term xe2x80x9camino protecting groupxe2x80x9d as used herein refers to groups such as those employed in peptide chemistry, such as an allyloxycarbonyl group (ALLOC), a lower alkoxycarbonyl group such as tert-butoxycarbonyl (t-BOC) and the like, a substituted lower alkoxycarbonyl group such as trichloroethoxycarbonyl, an optionally substituted aryloxycarbonyl group for example p-nitrobenzyloxycarbonyl or benzyloxycarbonyl (Z), an arylalkyl group such as triphenylmethyl (trityl), benzhydryl or benzyl, an alkanoyl group such as formyl, acetyl or benzoyl, a halogen-alkanoyl group such as trifluoroacetyl, or a silyl protective group such as the tert-butyldimethylsilyl group.
Preferred amino protecting groups are benzyloxycarbonyl, tert-butoxycarbonyl or allyloxycarbonyl.
An especially preferred amino protecting for R2 is the benzylocycarbonyl group.
The term xe2x80x9clower alkoxyxe2x80x9d signifies an alkyl group as defined above which is bonded via an oxygen atom. Examples are methoxy, ethoxy, propyloxy, butoxy, tert.butoxy and the like.
The term xe2x80x9carylxe2x80x9d as used herein denotes an optionally substituted phenyl group (Ph) in which one or more aryl hydrogen atoms can be substituted by one or more phenyl groups, alkyl groups, lower alkoxy groups, halogenated alkyl groups, halogen atoms or nitro. Examples are phenyl, o-tolyl, m-tolyl, p-tolyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl, p-trifluoromethylphenyl, o-trichloromethylphenyl, m-trichloromethylphenyl, p-trichmoromethylphenyl, p-fluorophenyl p-chlorophenyl, p-bromophenyl, p-nitrophenyl.
The term xe2x80x9caryloxyxe2x80x9d signifies an aryl group as defined above which is bonded via an oxygen atom. Examples are phenyloxy, benzyloxy and the like.
The term xe2x80x9clower alkoxycarbonylxe2x80x9d denotes lower alkoxy residues as defined, attached to a carbonyl group (xe2x80x94C(xe2x95x90O)). Examples are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.
The term xe2x80x9caryloxycarbonylxe2x80x9d denotes aryloxy residues as defined, attached to carbonyl group (xe2x80x94C(xe2x95x90O)). Examples are phenyloxycarbonyl and benzyloxycarbonyl.
The term xe2x80x9carylalkylxe2x80x9d as used herein denotes a hydrocarbon group in which one or more alkyl hydrogen atoms are substituted by an aryl group as defined. Examples are trityl, benzhydryl or benzyl.
The term xe2x80x9chydroxy protecting groupxe2x80x9d as used herein denotes an alkyl group, a cycloalkyl group or an arylalkyl group. A preferred hydroxy protecting group is an arylalkyl group, especially preferred is a triphenylmethyl (trityl) group.
The term xe2x80x9ccarboxylic acid protecting groupxe2x80x9d includes protecting groups which are usually used to replace a proton of the carboxyl group. Examples of such groups are described in Green T. Protective Groups in Organic Synthesis, Chapter 5, John Wiley and Sons, Inc. (1981), pp. 152-192. Examples of such protecting groups are: benzhydryl, tert.-butyl, p-nitrobenzyl, p-methoxybenzyl, methoxymethyl and the like. Benzhydryl is a preferred carboxylic acid protecting group.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein denotes a 3-6 membered saturated carbocyclic moiety, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclohexyl.
In step (a) of the reaction the asparagine derivatives of formula V (preparation see below) is treated with 0.5-2.0 equivalents, preferably 1.0-1.5 equivalents of a base such as NaH, NaOH or KOH, preferably with NaH, in an appropriate solvent to obtain the cyclic intermediate of formula A 
wherein * and R2 are as defined above.
Appropriate solvents for the cyclization reaction are ethers such as tetrahydrofuran, diethyl ether, dioxane or a mixture of the mentioned solvents, preferably tetrahydrofuran. Then, in a preferred embodiment of the invention, the intermediate of formula A is reacted with commercially available benzyl bromide in the presence of an appropriate solvent to obtain the 3-amino protected benzyl-2,5-dioxo-pyrrolidine of formula VI. Appropriate solvents are polar aprotic solvents such as dimethylsulfoxide (DMSO), dimethylacetamide or N,N-dimethylformamide (DMF), preferably DMF. The reaction is carried out at a temperature between about 0xc2x0 C. and about 50xc2x0 C., preferably between about 10xc2x0 C. and about 40xc2x0 C.
In another embodiment of the invention the intermediate of formula A is reacted with commercially available p-methoxybenzylbromide, 3,4-dimethoxybenzylbromide, trityl chloride, methoxy methyl chloride or allyl bromide under above-described reaction conditions or alternatively according to methods known from textbooks on organic chemistry (e.g. J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons) to obtain the corresponding 1-N-substituted 3-amino protected-2,5-dioxo-pyrrolidine of formula VI.
The reaction of step (a) can optionally be carried via a two step procedure. First, the asparagine derivatives of formula V is treated with 0.5-2.0 equivalents, preferably 1.0-1.5 equivalents of a base such as NaH, NaOH or KOH, preferably with NaH in an appropriate solvent to obtain the cyclic compound of formula A. Appropriate solvents for this first step are ethers such as tetrahydrofuran, diethyl ether, dioxane or a mixture of the mentioned solvents, preferably tetrahydrofuran. The reaction is carried out at a temperature between about xe2x88x9210xc2x0 C. and about 30xc2x0 C., preferably starting at 0xc2x0 C.; during the reaction the temperature is increased to room temperature. After the reaction, the reaction mixture is acidified to a pH in the range between 3.0 and 5.0, preferably between 3.5 and 4.5, and then the organic solvent is evaporated. Secondly, the compound of formula A is treated with a base such as NaH, NaOH or KOH, preferably with NaH in ethers such as tetrahydrofuran, diethyl ether, dioxane or a mixture of the mentioned solvents, preferably in tetrahydrofuran.
Then, in a preferred embodiment of the invention, the mixture is reacted with commercially available benzyl bromide in the presence of an appropriate solvent to obtain the 3-amino protected benzyl-2,5-dioxo-pyrrolidine of formula VI. Appropriate solvents for the reaction are polar aprotic solvents such as dimethylsulfoxide (DMSO), dimethylacetamide or N,N-dimethylformamide (DMF), preferably DMF. The reaction is carried out at a temperature between about xe2x88x9210xc2x0 C. and about 30xc2x0 C., preferably starting at 0xc2x0 C.; during the reaction the reaction temperature is increased to room temperature. After the reaction, the product is worked-up in a manner known in the art for example quenched with H2O and extracted with an aromatic solvent such as toluene, o-xylene, m-xylene, p-xylene or benzene preferably toluene, dried over anhydrous magnesium sulfate, sodium sulfate, calcium chloride, preferably magnesium sulfate and finally the organic solvent is evaporated.
In another embodiment of the invention the mixture is reacted with commercially available p-methoxybenzylbromide, 3,4-dimethoxybenzylbromide, trityl chloride, methoxy methyl chloride or allyl bromide under above-described reaction conditions or alternatively according to methods known from textbooks on organic chemistry (e.g. J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons) to obtain the corresponding 1-N-substituted 3-amino protected-2,5-dioxo-pyrrolidine of formula VI.
Asparagine derivatives of formula V are commercially available or can be synthesized according to methods known from textbooks on organic chemistry (e.g. J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons) for example starting with D- or L-asparagine (Fluka) protection of the free amino function and subsequent esterification to obtain the corresponding asparagine derivatives of formula V.
The advantage of carrying out the reaction of step (a) via a two step procedure is that the compounds of formula VI are obtained in higher yield. The two step procedure is also a part of the present invention.
In step (b) of the process the amino protecting group (R2) of the compounds of formula VI is removed under condition described below. Preferred amino protecting groups for R2 are benzyloxycarbonyl, tert-butoxycarbonyl or allyloxycarbonyl, most preferred benzyloxycarbonyl. The benzyloxycarbonyl amino protecting group is for example removed under hydrogenation conditions in the presence of a catalyst such as Pd/C (commercially available from Degussa) preferably with 10% Pd on activated carbon. The deprotection reactions are carried out in the presence of acetic acid, trifluoroacetic acid, ethanolic HCl, methanesulphonic acid or fluorosuphonic acid to obtain the corresponding amino salt of formula VII which is more stable than the free base and therefore can be stored without degradation. In a preferred embodiment acetic acid is used to prepare the acetic acid salt of formula VII. The reaction is carried out at a temperature between about 10xc2x0 C. and about 50xc2x0 C., preferably between about 20xc2x0 C. and about 40xc2x0 C.
Depending on the amino protecting groups the deprotection is carried out as follows:
The amino protecting groups may be cleaved off by acid hydrolysis (e.g. the tert-butoxycarbonyl or trityl group), e.g. aqueous formic acid, trifluoroacetic acid or by basic hydrolysis (e.g. the trifluoroacetyl group). Further protecting groups may be cleaved off by hydrazinolysis (e.g. the phthalimido group). The allyloxycarbonyl group may be cleaved off by Pd catalysed transfer to nucleophiles. The chloroacetyl, bromoacetyl and iodoacetyl groups are cleaved off by treatment with thiourea.
Amino protecting groups which are cleavable by acid hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. The reaction is carried out in the acid or in the presence of a co-solvent such as a halogenated lower alkane, e.g. methylene chloride. The acid hydrolysis is generally carried out at room temperature, although it can be carried out at a slightly higher or slightly lower temperature (e.g. a temperature in the range of about xe2x88x9230xc2x0 C. to 40xc2x0 C.). Protecting groups which are cleavable under basic conditions are generally hydrolyzed with dilute aqueous caustic alkali at 0xc2x0 C. to 30xc2x0 C. The chloroacetyl, bromoacetyl and iodoacetyl protecting groups can be cleaved off using thiourea in acidic, neutral or alkaline medium at about 0xc2x0 C. to 30xc2x0 C.
In step (c) of the process the amino salt compound of formula VII is treated with a base such as NaOH, KOH, Na2CO3 or K2CO3 preferably with NaOH in aqueous solution to adjust the pH in the ranges from 7.0 to 9.0, preferably in the range from 7.5 to 8.5 in the presence of a halogenated hydrocarbon such as monochloromethane or dichloromethane, preferably dichloromethane, to remove the acid and to obtain the intermediate acid free compound of formula VII. The intermediate is then worked-up by extraction with a halogenated hydrocarbon such as monochloromethane or dichloromethane, preferably dichloromethane and then the organic solvent is evaporated. Subsequently, the acid free derivative of formula VII is reduced with a reducing agent such as Vitride(copyright), NaBH4, LiBH4, LiAlH4, BH3xe2x80xa2THF, preferably with Vitride(copyright), to obtain the amino pyrrolidine of formula II. The reducing agents are commercially available from Aldrich or Fluka. The reaction is carried out in an aromatic solvent such as toluene, o-xylene, m-xylene, p-xylene or benzene, preferably with toluene at a reaction temperature between about xe2x88x9210xc2x0 C. and about 100xc2x0 C., preferably starting at 0xc2x0 C.; during the reaction the temperature is increased to 80xc2x0 C. Then, the mixture is cooled to a temperature between about xe2x88x9220xc2x0 C. and about 20xc2x0 C., preferably to a temperature between about xe2x88x9210xc2x0 C. and about 10xc2x0 C. and treated with a base such as sodium hydroxide in aqueous solution.
In a preferred embodiment of the process steps a-c are carried out for compounds wherein * signifies an asymmetric center with (R) configuration and R1 is methyl or ethyl, preferably methyl and R2 is benzyloxycarbonyl, tert-butoxycarbonyl or allyloxycarbonyl, preferably benzyloxycarbonyl and X is chlorine or bromine, preferably bromine.
The compounds of formula I-VII are important building blocks for the production of useful products in the chemical and pharmaceutical industry. In particular they are useful for the production of antibacterial substances for example vinylpyrrolidinone-cephalosporin derivatives as described in EP-A 0 849 269. Preferably compounds of formula I-VII are useful for the preparation of compounds of formula VIII 
wherein R3 is a hydroxy protecting group, R4 is a carboxylic acid protecting group, * is as defined above and R5 is an amino protecting group preferably a tert-butoxycarbonyl group or a group of formula B 
wherein R6 is preferably an unsubstituted straight chain or branched alkyl group containing 1 to 4 carbon atoms, more preferred methyl, ethyl or isopropyl and most preferred methyl.
The preparation of compounds of formula VIII is described in EP-A 0 849 269.
In the following examples the abbreviations used have the following signification""s.